The TAZ-TEAD Complex Modulates CD4~+ T Cells Differentiation By Altering Interaction Between The Transcription Factors RORγt And Foxp3

The Th17 cells and Treg cells have opposing roles in autoimmune diseases such as rheumatoid arthritis and Sjogren’s syndrome.The development of these two cell subsets is delicately balanced by cytokine signaling:TGFβ drives the expression of both of the key transcriptional regulators RORyt(Th17 cells)and Foxp3(Treg cells),and Th17 cells require further cytokine IL-6 signaling that induces the signal transducer STAT3 to prevent inhibition of the RORyt by Foxp3.The precise mechanisms by which STAT3 alleviates the repression of RORyt by Foxp3 were not clear.Here we find the MST-TAZ-TEAD axis,the core component of Hippo signaling,is required for the homeostasis of inflammatory Th17 cells and immunosuppressive Treg cells.Under Th17 cell-inducing conditions,TAZ expression is strongly induced by combined signaling via the signal transducers SMAD3 and STAT3 downstream of the cytokines TGFβ and IL6.TAZ acts in multiple ways to ultimately favor Th17 differentiation.First TAZ was a critical coactivator of RORyt.Simultaneously,TAZ destabilizes Foxp3 by limiting its acetylation,which leads to increased proteasome degradation of Foxp3.Finally,TAZ acts as a scaffold protein,disrupting Foxp3 mediated inhibition of RORyt activation.In contrast,under Treg cell-skewing conditions,TEAD1 expression and TEAD’s high-affinity binding to TAZ to sequester TAZ away from Foxp3 and RORyt,thereby enhance Tip60 mediated acetylation and stabilization of Foxp3 to further advance the development of Treg cells.The antagonistic sequestration of TEAD-TAZ also favors Foxp3 mediated inactivation of RORγt.Our results demonstrate members of Hippo family modulate CD4+Th cells fate by altering interactions between the transcription factors RORγt and Foxp3,and reveal a non-canonical role for Hippo signaling in immune homeostasis.